Integrins are a family of α/β heterodimeric transmembrane receptors found throughout metazoan development. Integrins are involved in various aspects of cellular behavior. For example, they mediate attachment to extracellular matrix (ECM) proteins and link the extracellular environment with intracellular signaling events. Integrin-mediated cell adhesions induce cell signaling that triggers calcium fluxes, activates tyrosine and serine/threonine protein kinases and inositol lipid metabolism, and regulates the activity of GTPases that control the actin cytoskeleton. Besides mediating stable adhesion, integrins play a role in cellular motility. Cell migration is essential for embryonic development, immune responses, and tissue repair.
In humans, there are 24 different functional integrins formed by the different combination of 18 alpha (α) and 8 beta (β) subunits. Many integrins bind to components of the extracellular matrix (ECM) such as laminins, collagens, and fibronectin. The integrin alpha-2 beta-1 (α2β1), for example, binds Type I collagen, the dominant ECM protein in the body. Integrin alpha-2 is one of the twelve α integrins that forms a functional receptor with the integrin beta 1 (β1) subunit. Integrin alpha-2 has only been found in vertebrates, and in humans, it is widely expressed on mesenchymal, epithelial and endothelial cells. Platelets also use integrin alpha-2 as their collagen receptor. Integrin alpha-2 has been implicated in hepatocarcinoma cell invasion across the fibrotic matrix microenvironment (Yang et al., Cancer Res., 63, 8312 (2003)), in metastasis of ovarian carcinoma spheroids (Shield et al., J. Carcinogenesis, 6, 11 (2007)), in metastasis to the liver (Yoshimura et al., Cancer Res., 69:18, 7320 (2009)), and in adhesion and cancer cell invasion in prostate cancer (Van Slambrouk et al., Int. J. Oncology, 34, 1717 (2009)).
Cancer remains a leading cause of death worldwide, with an estimated 500,000 Americans succumbing to the disease in 2010 (American Cancer Society. Cancer Facts & Figures 2010. Atlanta, American Cancer Society; 2010). There remains a need in the art for therapeutics, and methods of using such therapeutics, that are effective in treating, preventing, or ameliorating cancer cell proliferation.